USPTO Patents Application 10763377

ENP-074

WHAT IS CLAIMED:

1. A process comprising the step of reacting a macrocyclic compound characterized by at
least two nucleophilic moieties with a bridging component optionally in the presence of
catalyst thereby achieving a bridged macrocyclic product.

2. The process of claim 1, wherein the macrocyclic compound is a macrolide antibiotic.

3. The process of claim 1, wherein the macrocyclic compound is an erythromycin
derivative.

4. The process of claim 3, wherein the erythromycin derivative is azithromycin, desmethyl
azithromycin, roxithromycin, clarithromycin, telithromycin, or cethromycin.

5. The process of claim 1, wherein the macrocyclic compound is selected from:

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X Y

Re Rf

xm

K Rf

XIV

wherein

D is selected from -NHCH 2 -, -NHCHR,-, -NHCR3R4-, -NR,CH 2 -,-NHC(0)-, -
NRjQOK -NHC(S)-, or -NR,C(S)-;

Each Ri is independently selected from hydrogen, deuterium, a substituted or
5 unsubstituted, saturated or unsaturated aliphatic group, a substituted or unsubstituted, saturated
or unsaturated alicyclic group, a substituted or unsubstituted aromatic group, a substituted or
unsubstituted heteroaromatic group, saturated or unsaturated heterocyclic group;

R 3 and R4 is independently selected from the group consisting of hydrogen, acyl, a
substituted or unsubstituted, saturated or unsaturated aliphatic group, a substituted or
10 unsubstituted, saturated or unsaturated alicyclic group, a substituted or unsubstituted aromatic
group, a substituted or unsubstituted heteroaromatic group, saturated or unsaturated heterocyclic
group; or can be taken together with the nitrogen atom to which they are attached to form a
substituted or unsubstituted heterocyclic or heteroaromatic ring;

L is selected from hydrogen, a substituted or unsubstituted, saturated or unsaturated
15 aliphatic group, a substituted or unsubstituted, saturated or unsaturated alicyclic group, a
substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group,
or a substituted or unsubstituted heterocyclic group;

one of U or V is hydrogen and the other is independently selected from the group

* — CV /O.

J

consisting of: Ri, ORj, OC(0)Ri, OC(0)NR 3 R4, S(0) n Ri, K i or other

20 carbohydrate or sugar moiety;

or U and V, taken together with the carbon atom to which they are attached, are C=0;

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or UV and ReRf, taken together with the carbon atoms to which they are attached, are -
C(R,)=CH-;

one of J or G is hydrogen and the other is selected from: Rj, ORi, or NR3R4;

or J and G, taken together with the carbon atom to which they are attached, are selected
5 from: C=0, C=NRi, C=NOR 1? C=NO(CH 2 ) m Ri, ONNHR,, C=NNHCOR,, C=NNHCONR 3 R4,
C=NNHS(0) n Ri, or C=N-N=CHR,;

R a , R b , Rc, and R<j are independently selected from -Ri, -OR 1? -S(0) n Ri, -C(0)OR ls -
OC(0)R,, -OC(0)OR,, -C(0)R,, -C(0)NH-R,, -NHC(0)-R,, -N(R 3 )(R4), -NHC(0)-ORi, -
NHC(0)NH-R,, or -OC(0)NH-R,;
10 or R a and R b , R a and Rc, R a and R<j, R b and Rc, R b and R<j, or Rc and R<i, taken together

with the carbon atom or atoms to which they are attached, are selected from substituted or
unsubstituted alicyclic or substituted or unsubstituted heterocyclic;

one of Re and Rf is selected from hydrogen or methyl, and the other is independently
selected from halogen, deuterium, or Rj.
15 R h is hydroxy;

R g is selected from hydrogen, a substituted or unsubstituted, saturated or unsaturated
aliphatic group, a substituted or unsubstituted, saturated or unsaturated alicyclic group, a
substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group,
or a substituted or unsubstituted heterocyclic group;
20 or Rg and Rh, taken together with the carbon atom to which they are attached, are selected

from an epoxide, a carbonyl, a substituted or unsubstituted olefin, a substituted or unsubstituted
alicyclic, a substituted or unsubstituted heterocyclic;

W is NR3R4;

one of X and Y is hydrogen, substituted or unsubstituted aliphatic, and the other is
25 independently selected from: hydroxy, -SH, -NH 2 , or -NRiH;

or X and Y, taken together with the carbon atom to which they are attached, are selected
from: C=0, C=NR,, C=NOR,, C=NO(CH 2 ) m R,, C=NNHRi, C=NNHCOR], ONNHCONR3R4,
C=NNHS(0) n R,, or C=N-N=CHRi;

R p is selected from hydrogen, acyl, silane, or a hydroxy protecting group;
30 Xh is selected from hydrogen or halogen;

m is an integer; and

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n is 0, 1, or 2.

6. The process of claim 4, wherein, for the macrocylic compound, L is ethyl.

7. The process of claim 4, wherein, for the macrocylic compound, one of X and Y is
hydrogen and the other is selected from hydroxy or amino.

8. The process of claim 4, wherein, for the macrocylic compound, X and Y, taken together
with the carbon atom to which they are attached, are selected from C=0, C=NH, C=N-
OH, or C=N-NH 2 ;

9. The process of claim 4, wherein, for the macrocylic compound, R g is methyl.

10. The process of claim 4, wherein, for the macrocylic compound, Re is hydrogen and Rf is
selected from methyl, allyl, or propargyl.

11. The process of claim 4, wherein, for the macrocyclic compound, one of U and V is
hydrogen and the other is selected from -OH or -O-cladinose.

12. The process of claim 4, wherein, for the macrocylic compound, U and V, taken together
with the carbon atom to which they are attached, are C=0.

13. A bridged macrocyclic product produced by the process of claim 1.

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